The present invention relates to an improved process for preparing suture grade .beta.-glycolide, and, more particularly, to a process for purifying crude glycolide to a degree of purity required for use as a precursor of biologically absorbably, i.e., resorbable, surgical sutures. The product of the process is crystalline .beta.-glycolide which can be polymerized to polyglycolic acid, a material from which the sutures are fabricated.
Surgical sutures made from absorbable synthetic polymers have been developed as a replacement for "catgut" sutures which are produced from collagenous tissues of animals. Due to biological variations in these tissues, the "catgut" sutures produced from them can have inconsistencies in texture, uniformity of size, strength and rate of absorption into bodily fluids.
To be used as an alternative surgical suture, the synthetic polymers must be capable of being formed, i.e., extruded, into a fiber which is strong, easy to handle, non-toxic and which has uniform and predictable absorptive characteristics. One material which exhibits such characteristics is polyglycolic acid (PGA) of the chemical formula (I) EQU H--(O--CH.sub.2 C.dbd.O).sub.n --OH (I)
where n is 350-2400.
Among several methods by which PGA can be prepared, one route involves the polymerization of glycolide (II), ##STR1## Glycolide, the cyclic dimeric condensation product formed by dehydrating glycolic acid, is ordinarily converted to PGA by a reaction in which the ring is broken, followed by straight-chain polymerization. Such a process is described in by Schmitt et al., U.S. Pat. No. 3,442,871, and according to which, glycolide is heated in the presence of both an alcohol which functions as an initiator and stannous chloride dihydrate which serves as a catalyst.
For use as an effective surgical suture, PGA must retain its strength long enough for the wound to heal before substantial absorption occurs. PGA having an inherent viscosity in the range of from about 1.0 to about 1.6 possesses the desired characteristics for use as a surgical suture, e.g., strength, handleability, non-toxicity, uniform and predictable absorbability. Inherent viscosity is a property applicable to polymers in solution. A capillary viscometer is used to measure inherent viscosity and is calculated using the following formula: EQU Inherent Viscosity=[1n(t/t.sub.o)]/c
wherein
t=efflux time of the polymer solution; PA0 t.sub.o =efflux time of the pure solvent; PA0 c=concentration of glycolide in solution, expressed in grams/100 ml.
The term "suture-grade PGA" is used herein to mean PGA having an inherent viscosity in the range of about 1.0 to 1.6 and "suture-grade glycolide" designates a glycolide capable of being polymerized to yield suture-grade PGA. The term "crude glycolide" is used herein to mean any glycolide which is not of suture-grade quality.
To obtain suture-grade PGA, the glycolide from which the PGA is made must be of high purity. Commercially available glycolide ordinarily contains several trace contaminants and typically will yield PGA which has an inherent viscosity of less than 1.0, and this low of an inherent viscosity is unacceptable. Among the impurities in commercial glycolide are free glycolic acid, oligomers of glycolic acid, colorants and free water.
In its solid state, glycolide can exist in two polymorphic forms: .alpha.-glycolide and .beta.-glycolide. These two forms of glycolide are discussed in further detail by Schmitt et al. and in U.S. Pat. Nos. 3,435,008 and 3,457,280. Pure .alpha.-glycolide is of orthorhombic structure and appears as thin flakes, while .beta.-glycolide is monoclinic in structure and is present as larger, more massive particles.
A more specific distinction between the two polymorphic species is exhibited in their optical characteristics as compared by Schmitt et al.:
______________________________________ glycolide .beta.-glycolide ______________________________________ Refractive Indices: .alpha. 1.486 1.430 .beta. 1.506 1.552 .nu. 1.620 1.568 Optic Axial Angle: 2V 47.degree. 40' 37.degree. 20' ______________________________________
Schmitt et al. also disclose that, in the presence of atmospheric moisture, .beta.-glycolide will partially hydrolyze to a material which is then capable of initiating polymerization of the glycolide, i.e., there is no need for a potentially contaminating catalyst. In contrast, .alpha.-glycolide is generally inert to atmospheric moisture, and, thus, a catalyst is required to promote its polymerization.
In isolating either of these forms of glycolide, temperature can be a critical factor during formation of the crystals and their subsequent storage. As a rule, glycolide which is precipitated at temperatures below 42.degree. C. is of the .beta.-form, while at temperatures above 42.degree. C. the .alpha.-form is generated.
Several methods for purifying and isolating glycolide have been described in the prior art. U.S. Pat. No. 4,650,851, for example, describes a process purifying glycolide in which impure glycolide is dissolved in an organic solvent, such as methylene chloride or tetrahydrofuran. Alumina is then added to the solution forming a slurry in which the dissolved glycolide is in intimate contact with the alumina. Unless the alumina treatment is carried out under carefully controlled conditions, the desired degree of purification will not be achieved. After the slurry has been stirred for up to one hour, the alumina is filtered from the solution. The solvent is then evaporated, leaving purified glycolide.
U.S. Pat. No. 3,457,280 describes methods for isolating .alpha.-glycolide by which substantially pure .alpha.-glycolide can be obtained from either mixtures of .alpha.- and .beta.-glycolide or from substantially pure .beta.-isomer via either of two methods. According to one technique, the source glycolide is dissolved in an inert solvent and heated to a temperature above the transition temperature of 42.degree. C. Suitable solvents include hydroxyl-containing compounds such as n-propanol, n-butanol, isoamyl alcohol, hexanol, ethylene glycol and the like. The .alpha.-glycolide is obtained by recrystallization from the solvent at temperatures in excess of 42.degree. C. The .alpha.-glycolide can also be isolated by heating the glycolide source in a solid form to a temperature above the transition temperature.
U.S. Pat. No. 3,435,008 describes isolating substantially pure crystalline .beta.-glycolide from either mixtures of .alpha.- and .beta.-glycolide or from the substantially pure .alpha.-isomer via either of two methods. In one process the substrate is dissolved in an inert solvent, such as n-propanol, n-butanol, isoamyl alcohol, hexanol, ethylene glycol, and this solution is maintained below the transition temperature of 42.degree. C. Also described is a process for polymerizing the .beta.-glycolide to polyglycolic acid in the presence of atmospheric moisture. The use of PGA in surgical sutures is not described.
Japanese Pat. No. 59/148777 (Takayanagi et al.) describes a process for the purification of glycolide in which the glycolide is heated to a molten state and then added dropwise to a solvent such as ethyl acetate, chloroform, or isopropanol, which is maintained between 10.degree. C. and its boiling point. Upon addition to the solvent, some glycolide precipitates and forms a suspension which is then cooled to 20.degree. C. while being stirred, thus precipitating the remaining glycolide. The resulting slurry is filtered and separated using conventional methods and, if necessary, the glycolide may be washed with solvent, filtered and dried under reduced pressure.
In another process described in U.S. Pat. No. 3,763,190, glycolide is prepared in highly pure form from O-haloacetylglycolic acid salts by elimination of a mineral acid salt and attendant closure of the ring. The compound O-chloroacetylglycolic acid is converted to a salt and glycolide is then formed as the salt is heated in a vacuum-sublimation apparatus in which the glycolide condenses on a cool surface.
The present invention provides a convenient method for purifying crude glycolide in yields of 85% or higher, and the .beta.-glycolide which results is suture-grade glycolide, i.e., it can be polymerized to PGA which has an inherent viscosity greater than 1.0.